T cells modified to express tumor-directed chimeric antigen receptors (CARs) have shown clinical efficacy in treating both hematological malignancies and solid tumors. It is likely, however, that the most effective use of CAR-modified T cells will require additional engineering to enable them to overcome tumor immune escape mechanisms. One of these escape strategies is target antigen modulation under selective pressure. This phenomenon has been reported as a cause of failure in both preclinical and clinical studies using adoptively-transferred T cells with single antigen specificity to treat heterogeneous tumors.